Herpes simplex is a viral disease from the herpesviridae family caused by both Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, herpes labialis, the visible symptoms of which are commonly called cold sores or fever blisters, is an infection of the face or mouth. Herpes labialis, usually caused by HSV-1, occurs in approximately 90% of cases and affects 20-45% of the adult US population. There is one US Food and Drug Administration (US FDA) approved topical product, docosanol, which is currently available as a therapeutic treatment. Systemically administered acyclovir, penciclovir, valacyclovir or famciclovir are also approved for use in speeding the healing of herpes labialis. Since recurrences occur over the lifetime of infected patients, developing additional topical and systemic antiviral therapies is needed.
Genital herpes, known as herpes genitalis or simply as herpes (from HSV-2), is the second most common and painful form of herpes, although either of these virus may cause both infections. Other disorders, such as herpetic whitlow, herpes gladiatorum, ocular herpes, cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy, are all caused by herpes simplex viruses. Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual. In 2013 about 1.1 billion people (15.9%) had asymptomatic genital herpes and 47 million new cases of genital herpes occurred (WIKI).
Varicella zoster virus or varicella-zoster virus (VZV) is one of eight herpes viruses known to infect humans and vertebrates. VZV only affects humans and commonly causes chickenpox in children, teens and young adults whereas herpes zoster (shingles) occurs in adults and rarely in children. VZV is known by many names, including chickenpox virus, varicella virus, zoster virus, and human herpes virus type 3 (HHV-3). Shingles is characterized by a painful skin rash with blisters in a large localized area on one side of the body, which may take 2-4 weeks to heal. Ongoing nerve pain following the shingles infection may last for months. The shingles vaccine, Zostavax® (a trademark of Merck Sharp & Dohme Corp.) decreases the incidence of shingles by about half in those between the ages of 50 and 80. (WIKI) In 2017, the US FDA approved SHINGRIX® (trademark of GlaxoSmithKline Biologicals, S.A.), a vaccine indicated for prevention of shingles (herpes zoster) in adults aged 50 years and older with >90% efficacy. It is available worldwide.
Present Treatments
There are presently no known methods to eradicate the herpes virus from the body. The herpes virus survives, dormant in nerve cells, and can be reactivated at any time, causing another outbreak at or near the initial infection site. With time, the frequency and severity of herpes outbreaks may diminish as antiviral immunity in the host grows. The duration of a cold sore from first appearance to healing is about 10 days, even without treatment. The herpes genitalis outbreak may cover larger areas, and take 2-3 weeks when existing ulcers crust and heal.
There are no treatments for the outbreak of shingles in a person once it appears. Use of over-the-counter (OTC) analgesics or opioids alleviates pain (WIKI)
Topical Treatments
1-Docosanol, a 22 carbon straight-chain saturated fatty alcohol, also known as behenyl alcohol, used traditionally as an emollient, emulsifier and thickener in cosmetics, is approved by the US FDA as Abreva® (trademark of GlaxoSmithKline Consumer Healthcare), an antiviral agent for reducing the duration of cold sores caused by the herpes simplex virus. Pharmacological formulations of 1-docosanol are complex, due to its near zero aqueous solubility, and its anti-HSV activity is difficult to reproduce in vitro, as described (Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex; Mohammed H. Khalil, et al.; Proc. Natl. Acad. Sci. USA Vol. 88, pp. 10825-10829, December 1991). Other publications have used surfactants such as Pluronic F-68 or Tetronic 908 and in these papers, the 50% inhibition ranges merely from 4 mM to 15 mM. Even in dimethyl sulfoxide as solvent, 1-docosanol makes only a milky suspension (even after sonication).
1-Docosanol is thought to act by inhibiting the fusion of the human host cell with the viral envelope of the herpes virus, thus preventing its replication (WIKI). The drug is available OTC as a cream. It is reported to reduce the mean time of healing to 4.1 days. The side-effects are mild headaches. The most serious side effects, although rare, are allergic reactions, including difficulty breathing, confusion, facial swelling, fainting, dizziness, hives or chest pain (WIKI).
Acyclovir or aciclovir is an acycloguanosine antiviral marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax® (trademark of GlaxoSmithKline LLC), Xovir and Imavir, are the most commonly used systemic antiviral drugs. Cream preparations, 5%, are used primarily for labial herpes simplex. These formulations are not very effective, however. Also, the topical creams are difficult to apply evenly over the infected surface, undesirably visible, and sensed or intrusive on the mind. Primarily, acyclovir and its prodrug, valacyclovir, are excellent oral therapies widely used in treating herpes genitalis infections.
Trifluridine, a 3-deoxynucleoside, is the mainstay of therapy to treat severe herpes infections of the eye. It is usually prescribed in the form of eye drops, and instilled at least 5 times daily for a few days. Due to the complex synthesis of trifluoridine, these prescriptions are very expensive.
Clearly, there's need for effective new treatments to treat skin and ocular infections caused by the HSV and VZV viruses. It is also desirable if these treatments were water and/or glycols soluble, to be applied as eye drops for treating herpes simplex keratitis and as clear gels or creams to apply over areas of infections as in oral herpes and herpes genitalis. Clear gels are less visible, easier to apply due to lower viscosity, and more acceptable than creams to treat infections of herpes labiliasis. The gels may also be developed in the form of patches of dissolvable microneedles for transdermal drug delivery. Particularly useful would be oral and/or parenteral treatments to treat incipient cases of infections caused by the varicella zoster virus (VZV).